Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α1A/α1D-Adrenergic Receptor Antagonist with Potential Uroselective Profile

Abstract

Benign prostatic hyperplasia (BPH) is the most common male clinical problem impacting the quality of life of older men. Clinical studies have indicated that the inhibition of α1A-/α1D adrenoceptors might offer effective therapy in lower urinary tract symptoms. Herein, a limited series of arylsulfonamide derivatives of (aryloxy)ethyl alicyclic amines was designed, synthesized, and biologically evaluated as potent α1-adrenoceptor antagonists with uroselective profile. Among them, compound 9 (3-chloro-2-fluoro-N-([1-(2-(2-(2,2,2-trifluoroethoxy)phenoxy]ethyl)piperidin-4-yl)methyl)benzenesulfonamide) behaved as an α1A-/α1D-adrenoceptor antagonist (Ki(α1) = 50 nM, EC50(α1A) = 0.8 nM, EC50(α1D) = 1.1 nM), displayed selectivity over α2-adrenoceptors (Ki(α2) = 858 nM), and a 5-fold functional preference over the α1B subtype. Compound 9 showed adequate metabolic stability in rat-liver microsome assay similar to the reference drug tamsulosin (Clint = 67 and 41 µL/min/mg, respectively). Compound 9 did not decrease systolic and diastolic blood pressure in normotensive anesthetized rats in the dose of 2 mg/kg, i.v. These data support development of uroselective agents in the group of arylsulfonamides of alicyclic amines with potential efficacy in the treatment of lower urinary tract symptoms associated to benign prostatic hyperplasia.

Design, Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like Properties

“…Although replacement of the 4-F substituent present in the pilot compound 6 with the 3-Cl one (compound 7) decreased the affinity for α 2 -AR 5-fold (K i = 138 and 649, respectively), this modification was tolerated for interaction with the 5-HT 7 R. Regardless of the kind of central amine core, introducing a fluorine atom in the meta position to the 3-Cl-phenylsulfonyl moiety (i.e., 5-Cl, 2-F substitution pattern) improved the affinity of compounds 7 and 15 for both biological targets. In contrast to our previous findings [33], the replacement of one or both halogens with the electron-donating methoxy substituent decreased the affinity for α 2 -AR and 5-HT 7 R ligands (8 vs. 9 and 10 and 16 vs. 17).…”

“…Regardless of the kind of central amine core, introducing a fluorine atom in the meta position to the 3-Cl-phenylsulfonyl moiety (i.e., 5-Cl, 2-F substitution pattern) improved the affinity of compounds 7 and 15 for both biological targets. In contrast to our previous findings [33], the replacement of one or both halogens with the electron-donating methoxy substituent decreased the affinity for α2-AR and 5-HT7R ligands (8 vs. 9 and 10 and 16 vs. 17). [34] with binding experiments performed in rat cerebral cortex; e Data taken from [35] with binding experiments performer in cloned human receptors.…”

Indoline-6-Sulfonamide Inhibitors of the Bacterial Enzyme DapE

“…We were pleased that these two indoline hit structures provided mutual confirmation of one another. Furthermore, indolines are a privileged scaffold in medicinal chemistry, as there are several examples of indoline-containing drugs approved for a variety of treatments: advanced or transitional cell carcinoma of the urothelial tract (vinflunine) [ 18 ], glaucoma and severe anticholinergic toxicity (physostigmine) [ 19 ], and schizophrenia in adults (lumateperone) [ 20 , 21 ], or are under investigation, as for benign prostatic hyperplasia (BPH) [ 22 ]. Furthermore, sulfonamides are pervasive in agrochemicals and in pharmaceuticals across therapeutic areas [ 23 , 24 , 25 , 26 , 27 ], and primary sulfonamides have recently been leveraged as versatile intermediates [ 28 ].…”